Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenases, stromelysins and/or gelatinases (known as "matrix metalloproteinases", and herein referred to as MMPs) are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas and hemangiomas. However, the relative contributions of individual MMPs in any of the above disease states is not yet fully understood.
Metalloproteinases are characterised by the presence in the structure of a zinc(II) ionic site. It is now known that there exists a range of metalloproteinase enzymes that includes human fibroblast collagenase (Type 1), PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin-1, stromelysin-2 and PUMP-1 (J. F. Woessner, FASEB J, 1991, 5, 2145-2154). Many known MMP inhibitors are peptide derivatives, based on naturally occuring amino acids, and are analogues of the cleavage site in the collagen molecule. A paper by Chapman et. al (J. Med. Chem. 1993, 36, 4293-4301) reports some general structure/activity findings in a series of N-carboxyalkyl peptides. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics. Such compounds usually have a functional group capable of binding to the zinc(II) site in the MMP, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, sulphydryl, and oxygenated phosphorus (eg phosphinic acid and phosphonamidate including aminophosphonic acid) groups.
Two known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group and a carboxylic group respectively as their zinc binding groups. With a few exceptions, such known MMPs may be represented by the structural formula (I) ##STR2## in which X is the zinc binding hydroxamic acid (--CONHOH) or carboxylic acid (--COOH) group and the groups R.sub.1 to R.sub.5 are variable in accordance with the specific prior art disclosures of such compounds. Examples of patent publications disclosing such structures are given below.
In such compounds, it is generally understood in the art that variation of the zinc binding group and the substituents R.sub.1, R.sub.2 and R.sub.3 can have an appreciable effect on the relative inhibition of the metalloproteinase enzymes. The group X is thought to interact with metalloproteinase enzymes by binding to a zinc(II) ion in the active site. Generally the hydroxamic acid group is preferred over the carboxylic acid group in terms of inhibitory activity against the various metalloproteinase enzymes. However, the carboxylic acid group in combination with other substituents can provide selective inhibition of gelatinase (EP-489,577-A). The R.sub.1, R.sub.2 and R.sub.3 groups are believed to occupy respectively the P1, P1' and P2' amino acid side chain binding sites for the natural enzyme substrate. There is evidence that a larger R.sub.1 substituent can enhance activity against stromelysin, and that a (C.sub.1 -C.sub.6)alkyl group (such as iso-butyl) at R.sub.2 may be preferred for activity against collagenase whilst a phenylalkyl group (such as phenylpropyl) at R.sub.2 may provide selectivity for gelatinase over the other metalloproteinases.
The precise role of each of the various types of MMP in mediating different clinical disease conditions is not understood at present. However, there is some evidence that for some clinical end points individual MMP types may have a greater causative role than others. For the treatment of conditions mediated mainly by one MMP type, clearly it would be desirable to use an MMP inhibitor which selectively inhibited that MMP, or at least was significantly more potent as an inhibitor of that MMP than of other MMP types.
Tumour necrosis factor (herein referred to as "TNF") is a cytokine which is produced initially as a cell-associated 28 kD precursor. It is released as an active, 17 kD form, which can mediate a large number of deleterious effects in vivo. When administered to animals or humans it causes inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration can also cause cachexia and anorexia. Accumulation of excessive TNF can be lethal.
There is considerable evidence from animal model studies that blocking the effects of TNF with specific antibodies can be beneficial in acute infections, shock states, graft versus host reactions and autoimmune disease. TNF is also an autocrine growth factor for some myelomas and lymphomas and can act to inhibit normal haematopoiesis in patients with these tumours.
Compounds which inhibit the production or action of TNF are therefore thought to be potentially useful for the treatment or prophylaxis of many inflammatory, infectious, immunological or malignant diseases. These include, but are not restricted to, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, rheumatoid arthritis, multiple sclerosis, radiation damage, toxicity following administration of immunosuppressive monoclonal antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolar injury.
Since excessive TNF production has been noted in several diseases or conditions also characterised by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may have particular advantages in the treatment or prophylaxis of diseases or conditions in which both mechanisms are involved.
As mentioned above, MMP inhibitors have been proposed with hydroxamic acid or carboxylic acid zinc binding groups. The following patent publications disclose hydroxamic acid-based and/or carboxylic acid-based MMP inhibitors:
U.S. Pat. No. 4,599,361 (Searle) PA1 EP-A-0236872 (Roche) PA1 EP-A-0274453 (Bellon) PA1 WO 90/05716 (British Bio-technology) PA1 WO 90/05719 (British Bio-technology) PA1 WO 91/02716 (British Bio-technology) PA1 EP-A-0489577 (Celltech) PA1 EP-A-0489579 (Celltech) PA1 EP-A-0497192 (Roche) PA1 WO 92/13831 (British Bio-technology) PA1 WO 92/17460 (SmithKline Beecham) PA1 WO 92/22523 (Research Corporation Technologies) PA1 WO 93/09090 (Yamanouchi) PA1 WO 93/09097 (Sankyo) PA1 WO 93/20047 (British Bio-technology) PA1 WO 93/24449 (Celltech) PA1 WO 93/24475 (Celltech) PA1 EP-A-0574758 (Roche) PA1 EP-A-0575844 (Roche) PA1 WO 94/02446 (British Biotech) PA1 WO 94/02447 (British Biotech) PA1 WO 94/21612 (Otsuka) PA1 WO 94/21625 (British Biotech) PA1 WO 94/24140 (British Biotech) PA1 WO 94/25434 (Celltech) PA1 WO 94/25435 (Celltech) PA1 WO 95/04033 (Celltech) PA1 WO 95/04735 (Syntex) PA1 WO 95/04715 (Kanebo) PA1 R.sub.1 is (C.sub.1 -C.sub.6)alkyl; (C.sub.2 -C.sub.6)alkenyl; phenyl; substituted phenyl; phenyl (C.sub.1 -C.sub.6)alkyl; substituted phenyl(C.sub.1 -C.sub.6)alkyl; heterocyclyl; substituted heterocyclyl; heterocyclyl(C.sub.1 -C.sub.6)alkyl; substituted heterocyclyl(C.sub.1 -C.sub.6)alkyl; a group BSO.sub.n A- wherein n is 0, 1 or 2 and B is hydrogen or a (C.sub.1 -C.sub.6)alkyl, phenyl, substituted phenyl, heterocyclyl, (C.sub.1 -C.sub.6)acyl, phenacyl or substituted phenacyl group, and A represents (C.sub.1 -C.sub.6)alkyl; amino; protected amino; acylamino; OH; SH; (C.sub.1 -C.sub.6)alkoxy; (C.sub.1 -C.sub.6)alkylamino; di-(C.sub.1 -C.sub.6)alkylamino; (C.sub.1 -C.sub.6)alkylthio; aryl (C.sub.1 -C.sub.6)alkyl; amino(C.sub.1 -C.sub.6)alkyl; hydroxy(C.sub.1 -C.sub.6)alkyl, mercapto(C.sub.1 -C.sub.6)alkyl or carboxy(C.sub.1 -C.sub.6)alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl-group amidated; lower alkyl substituted by carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, or carboxy-lower alkanoylamino, PA1 R.sub.2 is a (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, phenyl(C.sub.1 -C.sub.6)alkyl, heteroaryl(C.sub.1 -C.sub.6)alkyl, cycloalkyl(C.sub.1 -C.sub.6)alkyl or cycloalkenyl(C.sub.1 -C.sub.6)alkyl group, any one of which may be optionally substituted by one or more substituents selected from (C.sub.1 -C.sub.6)alkyl, --O(C.sub.1 -C.sub.6)alkyl, --OCH.sub.2 Ph wherein the phenyl group may be optionally substituted, --S(C.sub.1 -C.sub.6)alkyl, halo and cyano (--CN); PA1 R.sub.3 is the characterising group of a natural or non-natural .alpha. amino acid in which any functional groups may be protected; PA1 R.sub.4 is a group --CHR.sup.x R.sup.y wherein R.sup.x and R.sup.y independently represent optionally substituted phenyl or monocyclic heteroaryl rings, which optionally may be linked covalently to each other by a bond or by a C.sub.1 -C.sub.4 alkylene or C.sub.2 -C.sub.4 alkenylene bridge, either of which may be interrupted by an O or S atom; PA1 R.sub.5 is hydrogen or a (C.sub.1 -C.sub.6)alkyl group; PA1 C atom carrying the R.sub.1 and X groups --S, PA1 C atom carrying the R.sub.2 group --R, PA1 C atom carrying the R.sub.3 group --S, PA1 C atom carrying the R.sup.x and R.sup.y groups --R or S PA1 (C.sub.1 -C.sub.6)alkyl, benzyl, hydroxybenzyl, benzyloxybenzyl, (C.sub.1 -C.sub.6)alkoxybenzyl, or benzyloxy(C.sub.1 -C.sub.6)alkyl group; and PA1 the characterising group of a natural .alpha. amino acid, in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated; and PA1 a group-Alk!.sub.n R.sub.6 where Alk is a (C.sub.1 -C.sub.6)alkyl or (C.sub.2 -C.sub.6)alkenyl group optionally interrupted by one or more --O--, or --S-- atoms or --N(R.sub.7)-- groups where R.sub.7 is a hydrogen atom or a (C.sub.1 -C.sub.6)alkyl group!, n is 0 or 1, and R.sub.6 is a optionally substituted cycloalkyl or cycloalkenyl group; or PA1 a benzyl group substituted in the phenyl ring by a group of formula --OCH.sub.2 COR.sub.8 where R.sub.8 is hydroxyl, amino, (C.sub.1 -C.sub.6)alkoxy, phenyl(C.sub.1 -C.sub.8)alkoxy, (C.sub.1 -C.sub.6)alkylamino, di((C.sub.1 -C.sub.6)alkyl)amino, phenyl(C.sub.1 -C.sub.6)alkylamino, the residue of an amino acid or acid halide, ester or amide derivative thereof, said residue being linked via an amide bond, said amino acid being selected from glycine, .alpha. or .beta. alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid; or PA1 a heterocyclic((C.sub.1 -C.sub.6)alkyl group, either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (C.sub.1 -C.sub.6)alkoxy, cyano, (C.sub.1 -C.sub.6)alkanoyl, trifluoromethyl (C.sub.1 -C.sub.6)alkyl, hydroxy, formyl, amino, (C.sub.1 -C.sub.6)alkylamino, di(C.sub.1 -C.sub.6)alkylamino, mercapto, (C.sub.1 -C.sub.6)alkylthio, hydroxy(C.sub.1 -C.sub.6)alkyl, mercapto(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkylphenylmethyl. PA1 R.sub.3 may be a group CR.sub.a R.sub.b R.sub.c in which: PA1 R.sub.c is hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, phenyl(C.sub.1 -C.sub.6)alkyl, PA1 or (C.sub.3 -C.sub.8)cycloalkyl, and R.sub.a and R.sub.b together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; or PA1 R.sub.a, R.sub.b and R.sub.c together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl); or PA1 R.sub.a and R.sub.b are each independently (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, phenyl(C.sub.1 -C.sub.6)alkyl, or a group as defined for R.sub.c below other than hydrogen, or R.sub.a and R.sub.b together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 3- to 8-membered heterocyclic ring, and R.sub.c is hydrogen, --OH, --SH, halogen, --CN, --CO.sub.2 H, (C.sub.1 -C.sub.4)perfluoroalkyl, --CH.sub.2 OH, --CO.sub.2 (C.sub.1 -C.sub.6)alkyl, --O(C.sub.1 -C.sub.6)alkyl, --O(C.sub.2 -C.sub.6)alkenyl, --S(C.sub.1 -C.sub.6)alkyl, --SO(C.sub.1 -C.sub.6)alkyl, --SO.sub.2 (C.sub.1 -C.sub.6)alkyl, --S(C.sub.2 -C.sub.6)alkenyl, --SO(C.sub.2 -C.sub.6)alkenyl, --SO.sub.2 (C.sub.2 -C.sub.6)alkenyl or a group --Q--W wherein Q represents a bond or --O--, --S--, --SO-- or --SO.sub.2 -- and W represents a phenyl, phenylalkyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.3 -C.sub.8)cycloalkylalkyl, (C.sub.4 -C.sub.8)cycloalkenyl, (C.sub.4 -C.sub.8)cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, --CN, --CO.sub.2 H, --CO.sub.2 (C.sub.1 -C.sub.6)alkyl, --CONH.sub.2, --CONH(C.sub.1 -C.sub.6)alkyl, --CONH(C.sub.1 -C.sub.6 alkyl).sub.2, --CHO, --CH.sub.2 OH, (C.sub.1 -C.sub.4)perfluoroalkyl, --O(C.sub.1 -C.sub.6)alkyl, --S(C.sub.1 -C.sub.6)alkyl, --SO(C.sub.1 -C.sub.6)alkyl, --SO.sub.2 (C.sub.1 -C.sub.6)alkyl, --NO.sub.2, --NH.sub.2, --NH(C.sub.1 -C.sub.6)alkyl, --N((C.sub.1 -C.sub.6)alkyl).sub.2, --NHCO(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.4 -C.sub.8)cycloalkenyl, phenyl or benzyl. PA1 Examples of particular R.sub.1 groups include methyl, ethyl, hydroxyl, methoxy allyl, thienylsulphanylmethyl, thienylsulphinylmethyl, thienylsulphonylmethyl and phthalimidomethyl. Presently preferred are compounds in which R.sub.1 is hydroxyl, methoxy, allyl or phthalimidomethyl. PA1 Examples of particular R.sub.2 groups include iso-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclohexylpropyl, phenylpropyl, phenylpropenyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, pyridine-4-ylpropyl, phenylbutyl, benzyloxybutyl, propyloxymethyl and propylsulphanyl. Presently preferred are compounds in which R.sub.2 is isobutyl, n-octyl, n-decyl, phenylpropyl, or phenylpropenyl. Variation of the R.sub.2 group may enhance the stromelysin-1 selectivity of a given compound relative not only to human fibroblast collagenase and 72 KDa gelatinase, but also relative to matrilysin. For example, groups R.sub.2 with chain lengths in excess of the equivalent of about 7 carbon atoms, eg n-octyl or longer, may be preferred over shorter R.sub.2 groups, eg isobutyl, for such stromelysin-1 selectivity. PA1 Examples of particular R.sub.3 groups include benzyl, iso-butyl or t-butyl, 1-benzylthio-1-methylethyl, 1-hydroxy-1-methylethyl and 1-mercapto-1-methylethyl. Presently preferred are compounds in which R.sub.3 is t-butyl, 1-hydroxy-1-methylethyl or 1-mercapto-1-methylethyl. PA1 R.sub.4 is a group --CHR.sup.x R.sup.y, and examples of R.sup.x and R.sup.y groups include optionally substituted phenyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, trizolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. Examples of particular R.sup.x and R.sup.y groups include phenyl, 2-fluorophenyl, 4-fluorophenyl, 2-pyridyl and 4-chlorophenyl. Also the R.sup.x and R.sup.y groups may be linked covalently to each other by a bond or by a C.sub.1 -C.sub.4 alkylene or C.sub.2 -C.sub.4 alkenylene bridge, and examples of such linked R.sup.x and R.sup.y groups include the case where R.sub.4 is an optionally substituted 9-H-fluoren-9-yl group. PA1 Examples of particular R.sub.5 groups include hydrogen, methyl and ethyl. Presently preferred are compounds in which R.sub.5 is hydrogen. PA1 (a) causing an acid of general formula (II) ##STR4## or an activated derivative thereof to react with hydroxylamine, O-protected hydroxylamine, or an N,O-diprotected hydroxylamine, or a salt thereof, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 being as defined in general formula (I) except that any substituents in R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 which are potentially reactive with hydroxylamine, O-protected hydroxylamine, the N,O-diprotected hydroxylamine or their salts may themselves be protected from such reaction, then removing any protecting groups from the resultant hydroxamic acid moiety and from any protected substituents in R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 or PA1 (b) deprotecting a diprotected hydroxamic acid derivative of formula (IIb) ##STR5## in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are as defined in general formula (I), R.sub.14 is an amino protecting group and R.sub.15 is a hydroxyl protecting group.